Many attempts have been done to establish a therapy for cancer, and such attempts have shown some advantageous therapeutic effects on several cancers. However, a method preventing cancer metastasis has not been established as yet.
Surgical therapy, radiotherapy and chemotherapy can be listed as a major method for therapy when one is diagnosed as getting cancer. When a patient shows clear abnormal symptom, most cancer probably becomes progressive and it is difficult to cure it. We can strongly believe that such difficulties is due to cancer metastasis and growing. Consequently, patient's condition after being cured mainly depends on the degree of cancer metastasis (Welch et al., Intern. J. Cancer, 43, 449, 1989). It is extremely difficult to cure cancer completely so long as such a cancer metastasis and growing are not suppressed. For example, in the case that stomach cancer becomes progressive, it is often that the cancer has already metastasized to lymph node, liver, lung and so forth. Such a phenomenon is occurred in breast cancer, it is reported that progressive cancer has metastasized to lymph node, which is adjacent to it, as well as bone marrow and lungs. Particularly, in regard to the epithelial cancer, the patient's condition after being cured depends on the degree of metastasis of cancer to lymph node (Shigeru Tsukakoshi, chemistry to cure cancer, Japan pharmaceutical society Pharmacia Review, No. 6).
Due to the above reasons, many attempts to elucidate detailed mechanism of cancer metastasis and apply its mechanism to therapy have done.
Cancer metastasis is constituted a complicated process in which cancerous cells departure from primary spot, infiltrate to peripheral tissues and grow in that metastasized tissues. This process is influenced by both factors of cancerous cell and host cell. In the former, the primary spot suffers from continuous gene alteration and consists of an uniformity cell mass showing various cytomorphosis, such as proliferation potency, drug sensitiveness, immunogenicity, configuration, etc. As factors of cancerous cell, metastasis ability, infiltration ability to periphery tissues, production of self growth factors from metastatic cancerous cell, and the like influence cancer metastasis. As factors of host cell, physical and anatomical condition in the blood, defense mechanism of immunocompetent cell, adhesion interaction between endothelial cell and blood platelet, growth factors from periphery metastasized tissues, and the like influence cancer metastasis.
It seems that on the serial process for cancer metastasis, expression and regulation of metastatic properties of cancerous cell is influenced by the interaction between cancerous cell and normal host cell, the interaction of cancerous cells with each together, and the interaction between cancerous cell and various biological components such as cell external matrix. Adhesion between cancerous cells with each together or between cancerous cell and normal cell is mediated by a cell adhesion molecule expressed on cell surface, and, as such a cell adhesion molecule, cadherin molecular group (Masatoshi Takeichi, molecular basis for tissue construction--role of cadherin for cell recognition--biochemistry, 59, 1, 1987), immune globulin molecular group, secretin molecular group (Springer, T. A., Nature, 346, 425, 1990) and so forth are known. On the other hand, adhesion molecule on cell surface including integulin molecular group contributes adhesion between cancerous cell and external matrix including glycoprotein such as fibronectin, laminin and collagen, and proteoglycan being bound with heparan sulfate, chondroitin sulfate etc.
Recently, it was made clear that cell external matrix molecule such as fibronectin or laminin strongly participated in cancer metastasis. It is shown that, after cell suffers from malignant transformation by oncogenic virus or chemical carcinogenesis agent etc., synthesis or accumulation into cell external of cell external matrix molecule, especially fibronectin, is decreased (Yamada, K. M. and Olden, K., Nature, 275, 179, 1978), expression of integrin molecule is decreased, and its adhesion ability to fibronectin is decreased (Plantefaber, L. C. and Hynes, R. O., Cell, 56, 281, 1989). It is also reported that fibronectin and laminin promote adhesion and metakinesis ability of cancerous cell (McCarthy, J. B., J. Cell Biol., 98, 1474, 1984).
Fibronectin and laminin molecule have domain configuration and let lots of functions disperse in the molecule. Configuration is made clear by biochemical or genetic engineering procedure, and existence of cell adhesion portion and receptor for it are discovered. RGD sequence in cell binding domain of fibronectin is cell recognition sequence (Pierschbacher, M. D., Nature, 309, 30, 1984), and the sequence exists and functions in lots of cell adhesion related molecules, and the receptor for the sequence is identified as alpha 5 beta 1 integrin receptor (Pytela, R., Cell, 40, 191, 1985).
Adhesion interaction between cell adhesion molecule and cell has been made clear, and recently application of cell adhesion peptide to inhibit cancer metastasis has been attempted. Humphries et al. show that GRGDS peptide as an adhesion signal of fibronectin inhibits experimental metastasis of melanoma cell to lung (Humphries, M. J., Science, 233, 467, 1986).
However, there are lots of problems to be solved in which clearance rate of the peptide in the blood after administration is fast and the peptide tends to be easily digested by enzyme for applying the peptide as a medicine (Saiki, I. et al., Jpn. J. Cancer Res., 84, 558, 1993).
Exploration of cancer metastasis inhibition materials as mentioned above is necessary to cure cancer completely. However, no substance being excellent medicine for cancer has obtained up to now.